U.S. patent application number 16/549645 was filed with the patent office on 2019-12-19 for compositions and methods for treating dementia.
This patent application is currently assigned to EIP Pharma, LLC. The applicant listed for this patent is EIP Pharma, LLC. Invention is credited to John Jahangir Alam.
Application Number | 20190381049 16/549645 |
Document ID | / |
Family ID | 60116397 |
Filed Date | 2019-12-19 |
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United States Patent
Application |
20190381049 |
Kind Code |
A1 |
Alam; John Jahangir |
December 19, 2019 |
COMPOSITIONS AND METHODS FOR TREATING DEMENTIA
Abstract
The present invention provides methods and compositions for
improving episodic memory and treating dementia.
Inventors: |
Alam; John Jahangir;
(Cambridge, MA) |
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Applicant: |
Name |
City |
State |
Country |
Type |
EIP Pharma, LLC |
Cambridge |
MA |
US |
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|
Assignee: |
EIP Pharma, LLC
Cambridge
MA
|
Family ID: |
60116397 |
Appl. No.: |
16/549645 |
Filed: |
August 23, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16145680 |
Sep 28, 2018 |
10420770 |
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16549645 |
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PCT/US2017/029012 |
Apr 21, 2017 |
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16145680 |
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62429705 |
Dec 2, 2016 |
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62325892 |
Apr 21, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/519 20130101;
A61P 25/28 20180101 |
International
Class: |
A61K 31/519 20060101
A61K031/519; A61P 25/28 20060101 A61P025/28 |
Claims
1. A method of improving episodic memory in a human subject that
has dementia, the method comprising administering to a subject in
need thereof a therapeutically effective amount of VX-745.
2. The method of claim 1, wherein the therapeutically effective
amount of VX-745 provides an average blood concentration of about 8
ng/mL.
3. The method of claim 1, wherein the therapeutically effective
amount is achieved by twice daily administration.
4. The method of claim 3, wherein the twice daily administering
occurs about 9 to 15 hours apart.
5. The method of claim 1, wherein the administering occurs within
about 30 to 60 minutes after the subject consumes food.
6. The method of claim 1 wherein an improvement in episodic memory
is measured by the Wechsler Memory Scale (WMS).
7. The method of claim 1 wherein an improvement in episodic memory
is measured by the Mini-Mental State Examination (MMSE).
8. The method of claim 7, wherein the human subject has a baseline
MMSE score from about 20 to about 28 prior to treatment.
9. The method of claim 7, wherein the treating of the human subject
results in at least a 3 point increase over the baseline MMSE
score.
10. A method of treating dementia in a human subject exhibiting a
decline in at least two of the following: memory; communication and
language; ability to focus and pay attention; reasoning and
judgment; and visual perception; the method comprising
administering to a subject in need thereof a therapeutically
effective amount of VX-745.
11. The method of claim 10, wherein the therapeutically effective
amount of VX-745 provides an average blood concentration of about 8
ng/mL.
12. The method of claim 10, wherein the therapeutically effective
amount is achieved by twice daily administration.
13. The method of claim 12, wherein the twice daily administering
occurs about 9 to 15 hours apart.
14. The method of claim 10, wherein the administering occurs within
about 30 to 60 minutes after the subject consumes food.
15. The method of claim 10, wherein VX-745 is administered at a
dose of about 40 mg.
16. A method of improving episodic memory in a human subject, the
method comprising administering to a subject in need thereof a
therapeutically effective amount of VX-745, wherein the subject has
a neurodegenerative disorder characterized by an increase in the
number and/or size of endosomes.
17. The method of claim 16, wherein the therapeutically effective
amount of VX-745 provides an average blood concentration of about 8
ng/mL.
18. The method of claim 16, wherein the therapeutically effective
amount is achieved by twice daily administration.
19. The method of claim 18, wherein the twice daily administering
occurs about 9 to 15 hours apart.
20. The method of claim 16, wherein VX-745 is administered at a
dose of about 40 mg.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation application of
U.S. application Ser. No. 16/145,680, filed Sep. 28, 2018, which is
a continuation of International Application No. PCT/US17/29012,
filed Apr. 21, 2017, which claims the benefit of U.S. Provisional
Application No. 62/325,892, filed Apr. 21, 2016, and U.S.
Provisional Application No. 62/429,705, filed Dec. 2, 2016, each of
which are hereby incorporated by reference in their entireties.
BACKGROUND
[0002] Dementia is a category of brain disease which is
characterized by a long term, often gradual, decrease in a person's
memory or other thinking skills that is great enough to affect
daily functioning. Common causes of dementia include Alzheimer's
disease, vascular dementia, Lewy body dementia, and frontotemporal
dementia. A person may suffer from more than one type of
dementia.
[0003] While symptoms can vary greatly, a diagnosis of dementia can
be made when one or more of the following core mental functions are
significantly impaired: memory, communication and language, ability
to focus and pay attention, reasoning and judgment, and visual
perception. Health care costs for dementia have been found to be
greater than that of any other disease. According to the National
Institutes of Health, total spending for people with dementia in
the last five years of life was more than a quarter-million dollars
per person.
[0004] The types of memory systems that may be affected by dementia
include: episodic memory, semantic memory, simple classical
conditioning, procedural memory, working memory, and priming (Gold,
C. A. and Budson, A. E. "Memory loss in Alzheimer's disease:
implications for development of therapeutics," Expert Rev.
Neurother. 8(12):1879-91 (2008)). Each of these types of memory
systems may be differentially affected depending on disease.
Episodic memory facilitates individuals to remember events, times
and places acquired through personal experience. Impairment of
episodic memory is often one of the earliest signs and symptoms of
dementia and directly linked to pathologic lesions within the
hippocampus, a critical region of the brain for episodic memory
formation. Of the memory systems most authors consider the episodic
memory system to be the most clinically relevant for dementia, as
impairments in this system can worsen memory for recent events,
leading to functional deficits (Tromp D, Duour A, Lithfous S,
Pebayle T, Despres O. "Episodic memory in normal ageing and
Alzheimer disease: Insights from imaging and behavioral studies."
Ageing Res Rev. (2015); 24:232-62).
[0005] Episodic memory can be assessed by clinical tests such the
Wechsler Memory Scale (WMS) or Hopkins Verbal Learning Test-Revised
(HVLT-R). In clinical practice, episodic memory may also be
assessed by components of the Mini-Mental State Examination
(MMSE).
[0006] The WMS is a neuropsychological test designed to measure
different memory functions in a human subject. The current version
of this test, the WMS-IV is made up of seven subtests: Spatial
Addition, Symbol Span, Design Memory, General Cognitive Screener,
Logical Memory(I & II), Verbal Paired Associates(I & II),
and Visual Reproduction(I & II). A person's performance is
reported as five Index Scores: Auditory Memory, Visual Memory,
Visual Working Memory, Immediate Memory, and Delayed Memory. The
latter two Index scores (i.e Immediate and Delayed Memory,
respectively) specifically assess episodic memory.
[0007] The HVLT-R is a measure of verbal episodic memory that
consists of 3 initial learning trials, a delayed recall trial and a
yes/no delayed recognition trial. The HVLT-R comes in 6 alternative
and parallel forms, thereby reducing the potential of a practice
effect.
[0008] The MMSE is a brief evaluation of orientation, registration,
attention, recall, language, and constructional praxis. The MMSE is
highly reproducible and is a useful tool for evaluating the mental
state and abilities of human patients. In addition to its value in
screening patients for dementia or patients at risk for dementia,
the MMSE is often used to document cognitive decline over time in
individual patients. (Clark, C. M., et al., "Variability in annual
Mini-Mental State Examination score in patients with probable
Alzheimer disease: a clinical perspective of data from the
Consortium to Establish a Registry for Alzheimer's Disease," Arch
Neurol. July; 56(7):857-62 (1999)).
SUMMARY
[0009] The present disclosure encompasses the surprising discovery
that treatment with VX-745 can improve mental function, such as
episodic memory, in a subject suffering from or at risk for
developing dementia relative to baseline mental function assessed
prior to treatment.
[0010] In the case of most progressive dementias, including
Alzheimer's disease, there is no cure, nor is there any treatment
that slows, stops, or reverses its progression. As a result, there
is a long-felt need for treatments for dementia, particularly
dementia associated with Alzheimer's disease. In particular, there
is a need for disease modifying drugs capable of slowing the rate
of decline and improving mental state and function, as assessed by
clinical scales, in patients suffering from or susceptible to
dementia, particularly dementia associated with Alzheimer's
disease.
[0011] As disclosed herein, in clinical studies, human subjects
treated with VX-745 were surprisingly found to have improvements in
episodic memory. In a 12-week clinical study, human subjects
treated with VX-745 demonstrated improvement in episodic memory as
assessed by the WMS Immediate and Delayed Recall. In a 6 week
clinical study, human subjects treated with VX-745 demonstrated
improvements in episodic memory as assessed by the HVLT-R.
[0012] The MMSE was utilized to assess patients for mild cognitive
impairment (MCI), or early signs of dementia that may be associated
with Alzheimer's disease, as well as episodic memory. The MMSE was
performed on more than one occasion during the study to ascertain
that treatment with VX-745 would not adversely affect the mental
status or function of patients, as well as to monitor whether there
was a reduction in the rate of cognitive decline of the human study
subjects. In both a 6-week 12-week clinical study patients
surprisingly showed improvement in MMSE scores as compared to
baseline. Those of skill in the art have previously thought that
reversal of dementia, particularly dementia associated with
neurodegenerative disease, may not be possible, particularly by a
monotherapy. (Lawrence, J., "Alzheimer's will be treated with
`cocktail` of drugs, predicts neuroscientist," The Pharmaceutical
Journal, Vol. 296, No. 7885 (online) (2016)).
[0013] In some embodiments, the invention provides methods of
improving episodic memory in a human subject; the methods
comprising administering to the subject a therapeutically effective
amount of VX-745.
[0014] In some embodiments, a human subject has dementia.
[0015] In some embodiments, a human subject is predisposed to
dementia.
[0016] In some embodiments, a human subject has mild cognitive
impairment (MCI).
[0017] In some embodiments, a human subject has a neurodegenerative
disorder.
[0018] In some embodiments, the invention provides methods of
treating dementia in a human subject exhibiting a decline in at
least one of the following: memory; communication and language;
ability to focus and pay attention; reasoning and judgment; and
visual perception; the methods comprising administering to the
subject a therapeutically effective amount of VX-745.
[0019] In some embodiments, the invention provides methods for
treating subjects susceptible to or at risk of developing or
progressing to dementia. In some embodiments, the human subject has
Alzheimer's disease. In some embodiments, the human subject has
mild cognitive impairment.
[0020] In some embodiments, the invention provides methods of
treating dementia in a human subject exhibiting a decline in at
least two of the following: memory; communication and language;
ability to focus and pay attention; reasoning and judgment; and
visual perception; the methods comprising administering to the
subject a therapeutically effective amount of VX-745.
[0021] In some embodiments, the treating results in one or more of
complete or partial reversal of existing memory deficits,
improvement in memory function (e.g., episodic memory function),
and a decrease in the rate of decline of memory function. In some
embodiments, the treatment results in both a decrease in the rate
of decline of memory function and improvement in memory
function.
[0022] In some embodiments, a therapeutically effective amount of
VX-745 provides an average blood concentration from about 1 ng/mL
to about 15 ng/mL, from about 1 ng/mL to about 10 ng/mL, from about
5 ng/mL to about 15 ng/mL, or from about 5 ng/mL to about 10 ng/mL.
In some embodiments, blood concentration is about 8 ng/mL.
[0023] In some embodiments, a therapeutically effective amount is
achieved by twice daily administration. In some embodiments, twice
daily administering occurs about 9 to 15 hours apart. In some
embodiments, twice daily administering occurs about 12 hours apart.
In some embodiments, administering occurs within about 30 to 60
minutes after a subject consumes food.
[0024] In some embodiments, VX-745 is administered at a dose of
from about 40 mg to about 125 mg. In some embodiments, VX-745 is
administered at a dose of 40 mg.
[0025] In some embodiments, a therapeutically effective amount of
VX-745 is from about 80 mg to about 500 mg per day. In some
embodiments, a therapeutically effective amount of VX-745 is from
about 80 mg to about 250 mg per day. In some embodiments, a
therapeutically effective amount is about 80 mg per day.
[0026] In some embodiments, VX-745 is in the form of a
pharmaceutically acceptable composition.
[0027] In some embodiments, VX-745 is administered to a human
subject that has a baseline mini mental state examination score
from about 20 to about 28 prior to treatment.
[0028] In some embodiments, treating of a human subject results in
at least a 3 point increase over the baseline mini mental state
examination score. In some embodiments, treating of a human subject
results in maintaining a baseline mini mental examination score. In
some embodiments, administration of VX-745 to a human subject
results in an improvement in one or more of: memory; communication
and language; ability to focus and pay attention; reasoning and
judgment; and visual perception. In some embodiments,
administration of VX-745 to a human subject results in an
improvement in two or more of: memory; communication and language;
ability to focus and pay attention; reasoning and judgment; and
visual perception. In some embodiments, administration of VX-745 to
a human subject results in an improvement in mental status and
function.
[0029] In some embodiments, methods are provided for administrating
VX-745 to modify pathophysiology associated with dementia and
improve one or more of: memory; communication and language; ability
to focus and pay attention; reasoning and judgment; and visual
perception.
[0030] In some embodiments, methods are provided for administering
VX-745 to modify pathophysiology associated with dementia and
reverse existing memory deficits. In some embodiments, methods are
provided for administering VX-745 to modify pathophysiology
associated with dementia and improve memory function. In some
embodiments, methods are provided for administering VX-745 to
modify pathophysiology associated with dementia and slow decline in
memory function. In some embodiments, methods are provided for
administering VX-745 to modify pathophysiology associated with
dementia and slow decline in and improve memory function.
[0031] In some embodiments, methods are provided for administrating
VX-745 to modify pathophysiology associated with Alzheimer's
disease and improve one or more of: memory; communication and
language; ability to focus and pay attention; reasoning and
judgment; and visual perception.
[0032] In some embodiments, methods are provided for administering
VX-745 to modify pathophysiology associated with Alzheimer's
disease and reverse existing memory deficits. In some embodiments,
methods are provided for administering VX-745 to modify
pathophysiology associated with Alzheimer's disease and improve
memory function. In some embodiments, methods are provided for
administering VX-745 to modify pathophysiology associated with
Alzheimer's disease and slow decline in memory function. In some
embodiments, methods are provided for administering VX-745 to
modify pathophysiology associated with Alzheimer's disease and slow
decline in and improve memory function.
[0033] In some embodiments, improvements are measurable by Mini
Mental State Examination scoring. In some embodiments, improvements
are measurable by Wechsler Memory Scale (WMS) scoring. In some
embodiments, improvements are measurable by Hopkins Verbal Learning
Test-Revised (HVLT-R) scoring. In some embodiments, improvements
are measurable by Clinical Dementia Rating (CDR) scoring. In some
embodiments, improvements are measurable by Columbia Suicide
Severity Rating Scale (C-SSRS) scoring. In some embodiments,
improvements are measurable by Alzheimer's Disease Assessment
Scale-Cognitive (ADAS-Cog) scoring. In some embodiments,
improvements are measurable by Alzheimer's Disease Cooperative
Study--Clinical Global Impression of Change (ADCS-CGIC) scoring. In
some embodiments, improvements are measurable by Alzheimer's
Disease Cooperative Study-Activities of Daily Living 19-item
(ADCS-ADL19) scoring. In some embodiments, improvements are
measurable by Alzheimer's Disease Cooperative Study-Activities of
Daily Living 23-item (ADCS-ADL23) scoring.
[0034] In some embodiments, improvements are measurable by
neuropsychological testing. In some embodiments, improvements are
measurable by radiological testing. In some embodiments,
improvements are measurable by evaluation of cerebrospinal fluid
(CSF). In some embodiments, improvements are measurable by
neuroimaging. In some embodiments, improvements are measurable by
one or more of magnetoencephalography (MEG), electroencephalogram
(EEG), and/or functional magnetic resonance imaging (fMRI).
[0035] In some embodiments, VX-745 is administered orally. In some
embodiments, VX-745 is administered parenterally.
[0036] In some embodiments, the invention provides compositions
comprising VX-745 for use in treating dementia in a human subject.
In some embodiments, a subject exhibits a decline in at least one,
or at least two, of the following: memory (e.g., episodic memory);
communication and language; ability to focus and pay attention;
reasoning and judgment; and visual perception.
[0037] In some embodiments, the composition for use comprises an
amount of VX-745 from about 40 mg to about 125 mg. In some
embodiments, the amount of VX-745 is 40 mg.
[0038] In some embodiments, the composition for use is administered
twice daily. In some embodiments, the composition for use is
formulated for oral delivery.
[0039] In some embodiments, the invention provides compositions for
use in the manufacture of a medicament for use in a method of
treating dementia.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] FIG. 1 depicts exemplary mini mental state examination
(MMSE) parameters used to assess patients to determine level of
mental function.
[0041] FIG. 2 depicts an exemplary graph of absolute change in MMSE
scores of four patients, treated with either 40 mg or 125 mg
VX-745.
[0042] FIG. 3 depicts the crystal structure of VX-745 bound to p38
MAPK.alpha..
[0043] FIG. 4 shows the patient demographic in a study to evaluate
VX-745 effects on endpoints including amyloid plaque load, PK/PD,
safety and tolerability, and synaptic function. Patients were
randomly assigned to one of the two VX-745 dose groups and
administered either 40 mg or 125 mg of VX-745, twice daily for 12
weeks.
[0044] FIG. 5 shows incidence of adverse events. VX-745 (40 mg or
125 mg) was administered twice daily for 12 weeks.
[0045] FIG. 6 panels A-C depict changes in MMSE scores for eight
patients treated with 40 mg and seven patients treated with 125 mg
VX-745.
[0046] FIG. 7 shows Wechsler Memory Scale (WMS) Analyses. (A) shows
three subsets of the WMS test (Logical Memory, Visual Reproduction,
and Verbal Paired Associates) and associated point-based
performance scores for immediate recall and delayed recall indices.
(B) depicts the Immediate Recall mean scores for subjects
administered 40 mg or 125 mg VX-745. (C) depicts the Delayed Recall
mean scores. Analyses were done by Wilcoxon sign rank test for
improvement.
[0047] FIG. 8 depicts responder analysis of dynamic [.sup.11C]PiB
PET.
[0048] FIG. 9 depicts analysis of quantitative dynamic
[.sup.11C]PiB PET. Shown are receptor parametric mapping
(RPM2)_BPND parameters from quantitative analysis of dynamic PET
Scan. Percent change in global cortical PET amyloid signal versus
baseline signal is depicted for <90 .mu.g*hr/mL and >90
.mu.g*hr/mL in a 12-hour plasma exposure to VX-754. Responders are
shown as circles with vertical lines.
[0049] FIG. 10 shows the patient demographic in a study to evaluate
VX-745 effects on endpoints including pharmacodynamic activity of
VX-745 in the central nervous system of patients with MCI due to AD
or with mild AD. Patients were administered either 40 mg or 125 mg
of VX-745, twice daily for 6 weeks. Other objectives included
evaluation of safety and tolerability, as well as plasma and CSF PK
profile.
[0050] FIG. 11 depicts CSF interleukin-10 (IL-10) mean change from
baseline on day 41 with time-matched day 42 plasma
concentration.
[0051] FIG. 12 depicts interleukin-8 (IL-8) levels (pg/mL) in CSF
over 24 hours at baseline and at day 41.
[0052] FIG. 13 comprising panels A-D, depicts Hopkins Verbal
Learning Test-Revised (HVLT-R) analyses. (A) shows mean group
scores for HVLT-R total recall. For each subject, baseline is
calculated as an average of the screening and day -2 value (n=8).
(B) shows individual subject scores for HVLT-R total recall. (C)
shows mean scores for HVLT-R total recall. (D) shows mean group
scores for HVLT-R delayed recall. For each subject, baseline is
calculated as an average of the screening and day -2 value (n=8).
(E) shows individual subject scores for HVLT-R delayed recall. (F)
shows mean scores for HVLT-R delayed recall.
[0053] FIG. 14 depicts MMSE individual subject scores at baseline
and day 40.
[0054] FIG. 15 depicts plasma brain-derived neurotrophic factor
(BDNF) levels at baseline and after 84 days (n=10 subjects). (A)
shows individual subject BDNF levels. (B) shows mean BDNF
levels.
[0055] FIG. 16 depicts EEA1 positive endosomes in 2N (Wild-Type) or
DS (Down's Syndrome) human fibroblasts after 24 hours exposure to
VX-745. (A) shows average number of endosomes per cell. (B) shows
average size of endosomes.
DEFINITIONS
[0056] Carrier: The term "carrier" refers to any chemical entity
that can be incorporated into a composition containing an active
agent (e.g., a p38 MAPK.alpha. inhibitor such as VX-745) without
significantly interfering with the stability and/or activity of the
agent (e.g., with a biological activity of the agent). In certain
embodiments, the term "carrier" refers to a pharmaceutically
acceptable carrier. An exemplary carrier herein is water.
[0057] Combination. As used herein, the term "combination,"
"combined," and related terms refers to a subject's simultaneous
exposure to two or more therapeutic agents in accordance with this
invention. For example, an agent (p38 MAPK.alpha. inhibitor such as
VX-745) may be administered with another therapeutic agent
simultaneously or sequentially in separate unit dosage forms or
together in a single unit dosage form. Accordingly, the present
invention provides, among other things, dosing regimens that
involve administering at least an agent of the present invention
(p38 MAPK.alpha. inhibitor such as VX-745), an additional
therapeutic agent, and a pharmaceutically acceptable carrier,
adjuvant, or vehicle (the pharmaceutically acceptable carrier,
adjuvant, or vehicle typically being in association with one or
both of the VX-745 and the additional therapeutic agent).
[0058] Dementia. The term "dementia" as used herein refers to a
decline in one or more of the following mental functions: memory;
communication and language; ability to focus and pay attention;
reasoning and judgment; and visual perception. In some embodiments,
dementia is associated with Alzheimer's disease.
[0059] Formulation. The term "formulation" as used herein refers to
a composition that includes at least one active agent (e.g., p38
MAPK.alpha. inhibitor such as VX-745) together with one or more
carriers, excipients or other pharmaceutical additives for
administration to a patient. In general, particular carriers,
excipients and/or other pharmaceutical additives are selected in
accordance with knowledge in the art to achieve a desired
stability, release, distribution and/or activity of active agent(s)
and which are appropriate for the particular route of
administration.
[0060] Neuroimaging. As used herein, the term "neuroimaging" refers
to a technique which directly or indirectly images the structure or
function of the brain. In some embodiments, the term "neuroimaging"
refers to a technique selected from computerized axial tomography
(CAT or CT), single photon emission computed tomography (SPECT),
positron emission tomography (PET), magnetic resonance imaging
(MRI) or functional magnetic resonance imaging (fMRI). In some
embodiments, a neuroimaging technique employs one or more imaging
agents such as radioactive, fluorescent or other detectable
ligands. In some embodiments, a fluorescent ligand is Pittsburgh
compound B
([N-Methyl-.sup.11C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole),
a fluorescent analog of thioflavin T. In some embodiments, a
radioactive ligand is Amyvid.RTM. (florbetapir .sup.18F) or
.sup.18F-flutemetamol. In some embodiments, the neuroimaging
technique is PET scan using Pittsburgh compound B as an imaging
agent. In some embodiments, the neuroimaging technique is PET scan
using Amyvid.RTM. as an imaging agent. In some embodiments, the
neuroimaging technique is PET scan using .sup.18F-flutemetamol as
an imaging agent.
[0061] Neuroimage. As used herein, the term "neuroimage" refers to
an image or picture generated by a neuroimaging technique. In some
embodiments, a "neuroimage" refers to one or more of CAT (or CT),
SPECT, PET, MRI or fMRI scans.
[0062] Parenteral. The term "parenteral" as used herein includes
subcutaneous, intravenous, intramuscular, intra-articular,
intra-synovial, intrasternal, intrathecal, intrahepatic,
intralesional and intracranial injection or infusion techniques.
Preferably, the compositions are administered orally,
intraperitoneally or intravenously. Sterile injectable forms of the
compositions of this invention may be aqueous or oleaginous
suspension. These suspensions may be formulated according to
techniques known in the art using suitable dispersing or wetting
agents and suspending agents. The sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally acceptable diluent or solvent, for example
as a solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium.
[0063] Patient. The term "patient" as used herein means a human to
which a formulation or composition comprising a formulation is
administered.
[0064] Pharmaceutically acceptable carrier, adjuvant, or vehicle.
The term "pharmaceutically acceptable carrier, adjuvant, or
vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that
does not destroy the pharmacological activity of the compound with
which it is formulated. Pharmaceutically acceptable carriers,
adjuvants or vehicles that may be used in the compositions of this
invention include, but are not limited to, ion exchangers, alumina,
aluminum stearate, lecithin, serum proteins, such as human serum
albumin, buffer substances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat.
[0065] Therapeutic agent. As used herein, the phrase "therapeutic
agent" refers to any agent that elicits a desired biological or
pharmacological effect when administered to a subject.
[0066] Therapeutically effective amount and effective amount. As
used herein, and unless otherwise specified, the terms
"therapeutically effective amount" and "effective amount" of an
agent refer to an amount sufficient to provide a therapeutic
benefit in the treatment, prevention and/or management of a
disease, disorder, or condition, e.g., to delay onset of or
minimize (e.g., reduce the incidence and/or magnitude of) one or
more symptoms associated with the disease, disorder or condition to
be treated. In some embodiments, a composition may be said to
contain a "therapeutically effective amount" of an agent if it
contains an amount that is effective when administered as a single
dose within the context of a therapeutic regimen. In some
embodiments, a therapeutically effective amount is an amount that,
when administered as part of a dosing regimen, is statistically
likely to delay onset of or minimize (reduce the incidence and/or
magnitude of) one or more symptoms or side effects of a disease,
disorder or condition.
[0067] Treat or Treating. The terms "treat" or "treating," as used
herein, refer to partially or completely alleviating, inhibiting,
delaying onset of, reducing the incidence of, yielding prophylaxis
of, ameliorating and/or relieving or reversing a disorder, disease,
or condition, or one or more symptoms or manifestations of the
disorder, disease or condition.
[0068] Unit Dose. The expression "unit dose" as used herein refers
to a physically discrete unit of a formulation appropriate for a
subject to be treated (e.g., for a single dose); each unit
containing a predetermined quantity of an active agent selected to
produce a desired therapeutic effect when administered according to
a therapeutic regimen (it being understood that multiple doses may
be required to achieve a desired or optimum effect), optionally
together with a pharmaceutically acceptable carrier, which may be
provided in a predetermined amount. The unit dose may be, for
example, a volume of liquid (e.g., an acceptable carrier)
containing a predetermined quantity of one or more therapeutic
agents, a predetermined amount of one or more therapeutic agents in
solid form (e.g., a tablet or capsule), a sustained release
formulation or drug delivery device containing a predetermined
amount of one or more therapeutic agents, etc. It will be
appreciated that a unit dose may contain a variety of components in
addition to the therapeutic agent(s). For example, acceptable
carriers (e.g., pharmaceutically acceptable carriers), diluents,
stabilizers, buffers, preservatives, etc., may be included as
described infra. It will be understood, however, that the total
daily usage of a formulation of the present invention will be
decided by the attending physician within the scope of sound
medical judgment. The specific effective dose level for any
particular subject may depend upon a variety of factors including
the disorder being treated and the severity of the disorder;
activity of specific active compound employed; specific composition
employed; age, body weight, general health, sex and diet of the
subject; time of administration, and rate of excretion of the
specific active compound employed; duration of the treatment; drugs
and/or additional therapies used in combination or coincidental
with specific compound(s) employed, and like factors well known in
the medical arts. In some embodiments, a unit dose of a p38
MAPK.alpha. inhibitor, such as VX-745 is about 1 mg, 3 mg, 5 mg, 10
mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 100 mg,
125 mg, or 250 mg.
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0069] Treatment for patients suffering from, or at risk of,
dementia, particularly dementia associated with Alzheimer's
disease, is limited. Physicians urgently need new strategies for
treatment of dementia.
[0070] The present invention provides, among other things,
compositions and methods for treating dementia and/or dementia
associated with Alzheimer's disease in a subject. In particular,
the present invention provides methods for promoting recovery of
function in a subject suffering from dementia and/or dementia
associated with Alzheimer's disease, by administering a composition
comprising the selective p38 MAPK.alpha. inhibitor VX-745. In some
embodiments, the invention provides methods for treating dementia
by administering a composition comprising the selective p38
MAPK.alpha. inhibitor VX-745.
[0071] In some embodiments, the invention provides compositions and
methods for treating subjects susceptible or at risk of development
or progression of dementia.
[0072] Various aspects of the invention are described in detail in
the following sections. The use of sections is not meant to limit
the invention. Each section can apply to any aspect of the
invention. In this application, the use of "or" means "and/or"
unless stated otherwise.
Dementia
[0073] Dementia is a category of brain disease which is
characterized by a long term, often gradual, decrease in a person's
memory or other thinking skills that is great enough to affect
daily functioning. Common causes of dementia include Alzheimer's
disease, vascular dementia, Lewy body dementia, and frontotemporal
dementia. A person may suffer from more than one type of
dementia.
[0074] Synaptic loss occurs early in neurodegenerative protein
misfolding diseases. These include, but are not limited to,
Alzheimer's and Parkinson's diseases, Lewy Body Dementia,
frontotemporal dementia, the tauopathies, amyotrophic lateral
sclerosis, and prion diseases. Each of these disorders has a
characteristic clinicopathological profile associated with the
accumulation of disease-specific misfolded protein in the brain and
central nervous system. Freeman, O. J. & Mallucci, G. R., "The
UPR and synaptic dysfunction in neurodegeneration," Brain Research,
1648 (Part B): 530-537 (2016).
[0075] Synaptic dysfunction is associated with impairment of memory
(e.g., episodic memory), mental status, and/or mental function.
During disease progression, increasing synaptic dysfunction and
loss leads eventually to neuronal cell death. Synaptic function may
be assessed and monitored by methodologies including, but not
limited to, magnetoencephalography (MEG), electroencephalogram
(EEG), and/or functional magnetic resonance imaging (fMRI).
[0076] Mechanistically, disruption of protein trafficking inside
neurons may be a pathogenic event, and possibly a common
pathophysiologic event, that underlies the development of memory
deficits and other cognitive deficits in Alzheimer's disease and
other dementias. Such physiologic defects may involve alterations
of lysosomal function, including autophagy-lysosomal mediated
protein degradation and endolysosomal (endocytosis) mediated
protein receptor turnover (Perik, A. & Annaert, W., "Early
etiology of Alzheimer's disease: tipping the balance toward
autophagy or endosomal dysfunction?," Acta Neuropathol 129:363-381
(2015); Nixon, R. A., "The role of autophagy in neurodegenerative
disease." Nat Medicine 19:983-997 (2013); Nixon, R. A. & Yang,
D. S., "Autophagy failure in Alzheimer's disease--locating the
primary defect," Neurobiol Dis 43(1): 38-45 (2011); Funk, K. E.
& Kuret, J., "Lysosomal Fusion Dysfunction as a Unifying
Hypothesis for Alzheimer's Disease Pathology," Int J of Alzheimer's
Dis (2012); Zhang, L., Sheng, R., Qin, Z., "The lysosome and
neurodegenerative diseases," Acta Biochim Biophys Sin 437-445
(2009); Sannerud, R. & Annaert, W., "Bin1 and CD2AP polarize Ab
generation in neurons," EMBO Rep 18:5-7 (2017)). As an example,
Familial Alzheimer's disease (FAD) demonstrates a connection
between abnormalities in lysosomal function and the development of
synaptic dysfunction and cognitive deficits. Expression of
FAD-associated genes in vitro leads to endolysosomal dysfunction
and in transgenic animal models with endosomal abnormalities
(specifically accumulation of early and enlarged endosomes)
associated with synaptic dysfunction, both of which precede
accumulation of amyloid plaque. Studies on human autopsy-derived
brain with Alzheimer's disease indicate that endosomal
abnormalities may be one of the earliest pathologic events in the
disease. Many of the major late onset Alzheimer's disease
associated genes (e.g. Apoe4, Bin1) have been linked to disruption
of endosomal function.
[0077] While symptoms can vary greatly, a diagnosis of dementia or
dementia associated with Alzheimer's disease may be made when at
least two of the following core mental functions are significantly
impaired: memory, communication and language, ability to focus and
pay attention, reasoning and judgment, and visual perception.
[0078] Types of memory systems include: episodic memory, semantic
memory, simple classical conditioning, procedural memory, working
memory, and priming (Gold, C. A. and Budson, A. E. "Memory loss in
Alzheimer's disease: implications for development of therapeutics,"
Expert Rev. Neurother. 8(12):1879-91 (2008)). Each of these types
of memory systems may be differentially affected depending on the
disease. Episodic memory, semantic memory, classical conditioning,
working memory, and/or priming may be disrupted in patients with
Alzheimer's disease. Impairment of episodic memory is one of the
earliest signs and symptoms of Alzheimer's disease.
[0079] Brain regions associated with episodic memory include the
medial temporal lobes, especially the hippocampus; the anterior and
dorsomedial nuclei of the thalamus; the fornix; the mammillary
bodies; the mammillothalamic tract and the retrosplenial cortex
(Gold, C. A. and Budson, A. E. "Memory loss in Alzheimer's disease:
implications for development of therapeutics," Expert Rev.
Neurother. 8(12):1879-91 (2008)). Other brain structures may also
function in episodic memory, including the diagonal band of Broca's
area and the presubiculum.
[0080] Impairment of episodic memory can be associated with
dementia or dementia associated with Alzheimer's disease. Episodic
memory is used to record, store/consolidate, and retrieve
information about personal experiences and the temporal and spatial
contexts of those experiences (Tromp, D. et al., "Episodic memory
in normal aging and Alzheimer disease: Insights from imaging and
behavioral studies," Ageing Res. Rev. (2015)). Episodic memory
includes autobiographical recollection and verbal or non-verbal
laboratory tasks involving recognition or recall (e.g., a list of
words). Several brain systems are thought to be involved in
episodic memory recording and retrieval, including the frontal
system and temporal hippocampal system, as well as other
structures, such as the parietal cortex, cerebellum, thalamus, and
cingulate gyrus. Various changes in the nervous system may be
related to decline in episodic memory, including: morphological
brain changes (e.g., alterations in the prefrontal cortex brain
region, which is associated with executive function); decrease in
white and gray matter volumes, neuronal numbers and size; reduced
efficiency of synaptic contacts and decreases in the concentrations
or signaling of neurotransmitters (e.g. dopamine, acetylcholine).
Episodic memory decline may also result from degradation of
cognitive resources, such as speed processing, inhibitory function
and attentional resources.
[0081] Dementia and/or Alzheimer's disease may be diagnosed and
monitored using one or more of the Mini-Mental State Examination
(MMSE), Wechsler Memory Scale (WMS), the Hopkins Verbal Learning
Test-Revised (HVLT-R), Clinical Dementia Rating (CDR), the Columbia
Suicide Severity Rating Scale (C-SSRS), Alzheimer's Disease
Assessment Scale-Cognitive (ADAS-Cog), neuropsychological testing,
radiological testing, evaluation of cerebrospinal fluid (CSF), and
neuroimaging.
[0082] Brain modifications related to episodic memory decline have
been studied by functional neuroimaging techniques, such as
functional Magnetic Resonance Imaging (fMRI) and Positron Emission
Tomography (PET). Cognitive aging studies and neurobiological
studies have characterized the effects of aging on behavioral
performance and effects on the brain, respectively. In vivo
neuroimaging techniques may be used to characterize the brain in
action and examine the links between behavior and function.
[0083] Episodic memory may be tested verbally or non-verbally.
Tests of experimental episodic memory encoding include verbal
material (words), non-verbal material (pictures, scenes, objects,
music, etc.), and the context under which the episodic memory was
acquired (e.g., source of the experience and contextual details).
In an example of episodic memory test, an individual is tested to
determine if they can associate the episodic memory (e.g., a word
from a list) with particular details (e.g., emotion, time place,
etc.). Neuroimaging techniques allow the study of the
neuroanatomical bases of the encoding process.
Storage/consolidation of episodic memory can be measured by delayed
recall in time of the previously recorded information (encoding)
and after an interfering activity.
[0084] Various tests can also be used to measure episodic memory
retrieval. In free recall, a list of items is presented to remember
during encoding (e.g., words, sounds or pictures) and the subject
is asked to recall as many items as possible in any order following
a delay of variable duration. Number of items correctly recalled
and number of mistakenly recalled items (e.g., words that were not
studied), are measured. In cued recall, a list of items to remember
is presented during encoding and is then tested with cues aimed at
helping a subject remember the material.
[0085] Episodic memory can be evaluated by measures of recall and
recognition. Assessment of episodic memory and learning can be
performed by providing specific verbal or visual information to a
test subject and asking the subject to either immediately provide
the information back ("immediate recall") or after a lag of 20 to
30 minutes ("delayed recall").
[0086] Symptomatic therapies have thus far failed to demonstrate
positive effects on episodic memory, as they appear to primarily
act by increasing attention, rather than impacting underlying
synaptic dysfunction.
[0087] There is a large population of human patients susceptible to
dementia, at risk of developing dementia, or are suffering from
dementia, particularly dementia associated with Alzheimer's
disease. Some patients have mild cognitive impairment (MCI),
sometimes referred to as "pre-dementia," with or without having
detectable plaques, tangles, or other hallmark pathologies of
Alzheimer's disease. There is also a clinically significant
percentage of patients clinically diagnosed with Alzheimer's
disease that do not display .beta.-amyloid accumulation even though
neurodegeneration is in progress. (Castello, M. A., et al., "Moving
beyond anti-amyloid therapy for the prevention and treatment of
Alzheimer's disease," BMC Neurology 14:169 (2014)).
[0088] In some embodiments, patients may be diagnosed with
susceptibility to dementia, at risk of development of dementia,
dementia, and/or MCI (e.g., pre-dementia), and monitored using one
or more of the mini-mental state examination (MMSE), Wechsler
Memory Scale (WMS), the Hopkins Verbal Learning Test-Revised
(HVLT-R), Clinical Dementia Rating (CDR), the Columbia Suicide
Severity Rating Scale (C-SSRS), Alzheimer's Disease Assessment
Scale-Cognitive (ADAS-Cog), neuropsychological testing,
radiological testing, and neuroimaging.
[0089] In some embodiments, the present invention provides a method
of stabilizing or improving one or more of: memory (e.g., episodic
memory), communication and language, ability to focus and pay
attention, reasoning and judgment, and visual perception. In some
embodiments, the present invention provides a method of stabilizing
or improving at least two of: memory, communication and language,
ability to focus and pay attention, reasoning and judgment, and
visual perception.
[0090] The MMSE is a questionnaire used extensively in clinical and
research settings to measure mental function. It is commonly used
to screen for dementia, and to assess the severity and progression
of dementia. The MMSE is an effective way to document a human
subject's response to treatment. The test examines functions
including registration, attention and calculation, recall,
language, ability to follow simple commands and orientation.
Exemplary mini-mental state examination parameters are provided in
FIG. 1.
[0091] The WMS is a neuropsychological test designed to measure
different memory functions in a human subject. The current version
of this test, the WMS-IV is made up of seven subtests: Spatial
Addition, Symbol Span, Design Memory, General Cognitive Screener,
Logical Memory(I & II), Verbal Paired Associates(I & II),
and Visual Reproduction(I & II). A person's performance is
reported as five Index Scores: Auditory Memory, Visual Memory,
Visual Working Memory, Immediate Memory (Recall), and Delayed
Memory (Recall). Immediate Recall and Delayed Recall Index scores
reflect episodic memory function.
[0092] The Hopkins Verbal Learning Test-Revised (HVLT-R) is a
measure of verbal episodic memory that consists of 3 initial
learning trials, a delayed recall trial and a yes/no delayed
recognition trial. The HVLT-R comes in 6 alternative and parallel
forms, thereby reducing the potential of a practice effect.
[0093] The Clinical Dementia Rating (CDR) measures dementia
severity by examining 6 domains: Memory, Orientation, Judgment and
Problem-Solving, Community Affairs, Home and Hobbies, and Personal
Care. Informants are administered a structured interview, to
collect information about the participants daily life in these 6
areas. Scoring is done on a 3 point scale for each of the 6 domains
and an overall box score is obtained assessing overall dementia
severity (sum of box, SOB).
[0094] The Columbia Suicide Severity Rating Scale (C-SSRS) is a
questionnaire for suicide assessment that can be used for subjects
with dementia.
Alzheimer's Disease
[0095] Alzheimer's disease is a leading cause of dementia.
Alzheimer's disease pathology is characterized by the deposition of
extracellular amyloid plaques in the brain parenchyma and
neurofibrillary tangles within neurons, along with neuronal and
synaptic loss.
[0096] Age and APOE4 genotype are the two greatest risk factors for
Alzheimer's disease. As many as six cognitive domains are affected
in individuals with Alzheimer's disease: memory, executive
functioning, language, visuospatial functioning, attention and
affect.
[0097] Mild cognitive impairment (MCI) is a preclinical period of
Alzheimer's Disease, during which early and mild cognitive deficits
can be recognized. In approximately 50% of individuals with MCI,
Alzheimer's Disease pathology can evolve within a few years.
Deficits in episodic memory, including disorders of encoding and
storage, appear in the very early stages (e.g. MCI) of Alzheimer's
Disease. During the course of progression to Alzheimer's Disease,
affected brain regions also progress. In the first stages of the
disease (i.e., MCI), the entorhinal cortex and associated
structures in the anterior medial temporal lobe (MTL) are affected,
with AD lesions progressing to the parietal cortex and neocortex,
and then the frontal lobe.
[0098] There is currently no therapy available for Alzheimer's
disease that reverses and/or slows disease progression. Synaptic
dysfunction has emerged as an important therapeutic objective for
AD disease modification. Therapeutic interventions that target
synaptic dysfunction have the potential to both reverse existing
functional deficits and slow further decline.
[0099] Synaptic dysfunction in the brain region responsible for
memory formation (the hippocampus) is a pathogenic event that
underlies the development of AD-related memory disorders
(Gallagher, M. & Koh, M. T. "Episodic Memory on the Path to
Alzheimer's Disease." Curr. Opin. Neurobiol. 21(6): 929-934 (2011);
Gold, C. A., & Budson, A. E., "Memory loss in Alzheimer's
disease: implications for development of therapeutics." Expert Rev
Neurother. 8(12): 1879-1891 (2008)), which manifests itself as
disruption in a very specific hippocampal-dependent function called
"episodic memory".
[0100] Acetylcholinesterase inhibitors are currently prescribed for
treatment of the cognitive impairments in Alzheimer's disease.
These inhibitors may improve cognitive functioning by increasing
neurotransmitter concentration at cholinergic synapses. Examples of
acetylcholinesterase inhibitors include donepezil, galantamine,
rivastigmine and tacrine.
[0101] Other therapies for Alzheimer's disease may include
memantine, a NMDA receptor antagonist, and monoclonal antibodies or
antibody fragments against AP.
VX-745
[0102] Many extracellular stimuli, including pro-inflammatory
cytokines and other inflammatory mediators, elicit specific
cellular responses through the activation of mitogen-activated
protein kinase (MAPK) signaling pathways. MAPKs are
proline-targeted serine-threonine kinases that transduce
environmental stimuli to the nucleus. Once activated, MAPKs
activate other kinases or nuclear proteins through phosphorylation,
including potential transcription factors and substrates. The four
isoforms (.alpha., .beta., .delta., and .gamma.) of p38 MAP kinase
comprise one specific family of MAPKs that mediate responses to
cellular stresses and inflammatory signals.
[0103] The role of p38 MAPK in the various stages of inflammation
has prompted the discovery of several compounds capable of
inhibiting p38 (SB203580, RWJ 67657, L-167307, VX-745, RPR200765A
and others). (See, e.g., Kumar et al., "p38 MAP Kinases: Key
Signaling Molecules as Therapeutic Targets for Inflammatory
Diseases," Nature Reviews, 2:717-726 (2003); Brown et al., "p38 MAP
kinase inhibitors as potential therapeutics for the treatment of
joint degeneration and pain associated with osteoarthritis," J.
Inflammation 5:22 (2008)). These pharmacological inhibitors are
cytokine-suppressive anti-inflammatory drugs responsible for in
vitro and in vivo inhibition of lipopolysaccharide-induced tumor
necrosis factor-.alpha. (TNF-.alpha.) production, and have been
developed in accordance with the primary pharmacologic action
presumed to being reduction of inflammation; for example, in
clinical studies doses were administered to achieve blood
concentrations that met or exceeded the whole blood IC50
(inhibitory concentration for 50% maximal effect) for inhibition of
cytokine (IL-1.beta. or TNF.alpha.).
[0104] VX-745 is a selective small-molecule inhibitor of the alpha
isoform of p38 MAPK, previously developed by Vertex Pharmaceuticals
for the treatment of rheumatoid arthritis (RA). FIG. 3 depicts the
crystal structure of VX-745 bound to p38 MAPK.alpha..
##STR00001##
[0105] Without wishing to be bound by theory, it is believed that
the clinical failures of p38 MAPK.alpha. inhibitors to treat
chronic inflammatory conditions such as rheumatoid arthritis are
due to redundancy of the inflammatory (cytokine production)
pathways. Such redundancy results in the upregulation of feedback
loops when p38 MAPK-mediated cytokine production is chronically
inhibited, leading to an overall lack of efficacy.
[0106] Without wishing to be bound by theory, as indicated by
Example 4, it is believed that VX-745 may act to improve episodic
memory by reversing impaired endolysosomal function within neurons
that leads to synaptic dysfunction within the hippocampus, a region
of the brain responsible for proper episodic memory function.
Methods
[0107] In certain embodiments, a provided method comprises
administering to a human subject in need thereof VX-745, or a
pharmaceutically acceptable composition thereof, at a dose
providing an average blood concentration from about 1 to about 15
ng/mL. In some embodiments, the human subject in need thereof is
suffering from dementia. In some embodiments, the human subject is
suffering from dementia associated with Alzheimer's disease. In
some embodiments, a provided method comprises administering to a
human subject in need thereof a dose of VX-745, or a
pharmaceutically acceptable composition thereof, providing an
average blood concentration of from about 1 ng/mL to about 15
ng/mL, from about 1 ng/mL to about 10 ng/mL, from about 5 ng/mL to
about 15 ng/mL, or from about 5 ng/mL to about 10 ng/mL.
[0108] In some embodiments, a provided method comprises
administering to a human subject in need thereof a dose of VX-745,
or a pharmaceutically acceptable composition thereof, providing an
average blood concentration of 1 ng/mL, 2 ng/mL, 3 ng/mL, 4 ng/mL,
5 ng/mL, 6 ng/mL, 7 ng/mL, 8 ng/mL, 9 ng/mL, 10 ng/mL, 11 ng/mL, 12
ng/mL, 13 ng/mL, 14 ng/mL, or 15 ng/mL.
[0109] In some embodiments, a provided method comprises
administering to a human in need thereof a dose of VX-745, or a
pharmaceutically acceptable composition thereof, providing an
average blood concentration of about 8 ng/mL.
[0110] In certain embodiments, the present invention provides a
method of treating dementia in a human subject comprising
administering to human subject exhibiting a decline in at least two
of the following: memory; communication and language; ability to
focus and pay attention; reasoning and judgment; and visual
perception; a dose of VX-745, or a pharmaceutically acceptable
composition thereof, providing an average blood concentration about
1 ng/mL to about 15 ng/mL, from about 1 ng/mL to about 10 ng/mL,
from about 5 ng/mL to about 15 ng/mL, or from about 5 ng/mL to
about 10 ng/mL.
Pharmaceutical Compositions
[0111] In some embodiments, a provided method comprises
administering to a patient a pharmaceutical composition comprising
VX-745 together with one or more therapeutic agents and a
pharmaceutically acceptable carrier, adjuvant, or vehicle. In some
embodiments, the present invention provides a pharmaceutical
composition comprising a dose of VX-745 together with one or more
therapeutic agents and a pharmaceutically acceptable carrier,
adjuvant, or vehicle, wherein the dose of VX-745 results in an
average blood concentration of from about 1 ng/mL to about 15
ng/mL, from about 1 ng/mL to about 10 ng/mL, from about 5 ng/mL to
about 15 ng/mL, or from about 5 ng/mL to about 10 ng/mL.
[0112] In some embodiments, the present invention provides a
pharmaceutical composition comprising a dose of VX-745 together
with one or more therapeutic agents and a pharmaceutically
acceptable carrier, adjuvant, or vehicle, wherein the dose of
VX-745 results in an average blood concentration of about 1 ng/mL,
2 ng/mL, 3 ng/mL, 4 ng/mL, 5 ng/mL, 6 ng/mL, 7 ng/mL, 8 ng/mL, 9
ng/mL, 10 ng/mL, 11 ng/mL, 12 ng/mL, 13 ng/mL, 14 ng/mL, or 15
ng/mL.
[0113] In certain embodiments, pharmaceutically acceptable
compositions of this invention are formulated for oral
administration. Pharmaceutically acceptable compositions of this
invention may be orally administered in any orally acceptable
dosage form including, but not limited to, capsules, caplets,
tablets, aqueous suspensions or solutions. In the case of tablets
for oral use, carriers commonly used include lactose and corn
starch. Lubricating agents, such as magnesium stearate, are also
typically added. For oral administration in a capsule form, useful
diluents include lactose and dried cornstarch. When aqueous
suspensions are required for oral use, the active ingredient is
combined with emulsifying and suspending agents. If desired,
certain sweetening, flavoring or coloring agents may also be
added.
[0114] The quantities of the compounds of the present invention
that are combined with the carrier materials to produce a
composition in a single dosage form will vary depending upon the
patient and the particular mode of administration. Preferably,
provided compositions should be formulated so that a dosage of
between 1-500 mg/day of VX-745 can be administered to a patient
receiving these compositions. Examples of compositions include
compositions formulated to administer dosages of between 1-10 mg,
10-25 mg or 25-50 mg or 125-250 mg of VX-745 to the patient
receiving these compositions. In some embodiments, the composition
is formulated into doses containing 1 mg, 3 mg, 5 mg, 10 mg, 20 mg,
25 mg, 30 mg, 40 mg, 50 mg, 80 mg, 100 mg, 125 mg, or 250 mg of the
active composition. Dosing regimens for these formulations may
include but are not limited to single administration dosing, once,
twice, or three times daily dosing, weekly dosing, and monthly
dosing. In some embodiments, a provided composition is formulated
to provide 40 mg/dose of VX-745. In some embodiments, a provided
composition is formulated to provide 80 mg/dose of VX-745. In some
embodiments, a provided composition is formulated to provide 100
mg/dose of VX-745. In some embodiments, a provided composition is
formulated to provide 125 mg/dose of VX-745. In some embodiments, a
provided composition is formulated to provide 250 mg/dose of
VX-745. In some embodiments, a provided composition is formulated
to provide 80 mg/day of VX-745. In some embodiments, a provided
composition is formulated to provide 250 mg/day of VX-745.
[0115] It should also be understood that a specific dosage and
treatment regimen for any particular patient will depend upon a
variety of factors, including the activity of the specific compound
employed, the age, body weight, general health, sex, diet, time of
administration, rate of excretion, drug combination, and the
judgment of the treating physician and the severity of the
particular disease being treated. The amount of a compound of the
present invention in the composition will also depend upon the
particular compound in the composition.
Dosing
[0116] In some embodiments, a compositions are administered in a
therapeutically effective amount and/or according to a dosing
regimen that is correlated with a particular desired outcome (e.g.,
with treating or reducing risk for disease).
[0117] Any provided composition as described herein may be
administered by any appropriate route. In some embodiments,
provided compositions as described herein is administered
intravenously. In some embodiments, provided compositions as
described herein is administered subcutaneously. As used herein,
the term "subcutaneous tissue" is defined as a layer of loose,
irregular connective tissue immediately beneath the skin. For
example, the subcutaneous administration may be performed by
injecting a composition into areas including, but not limited to,
thigh region, abdominal region, gluteal region, or scapular region.
In other embodiments, provided compositions as described herein is
administered by direct administration to a target tissue, such as
heart or muscle (e.g., intramuscular), nervous system (e.g., direct
injection into the brain; intraventricularly; intrathecally), or
other target tissue such as the liver, kidney, etc. Alternatively,
provided compositions as described herein can be administered via
inhalation, intraperitoneally, parenterally, intradermally,
transdermally, or transmucosally (e.g., orally or nasally). More
than one route can be used concurrently, if desired.
[0118] In some embodiments, provided compositions are administered
in a therapeutically effective amount and/or according to a dosing
regimen that is correlated with a particular desired outcome (e.g.,
treat dementia, improve daily function, increase in MMSE score,
etc.).
[0119] Particular doses or amounts to be administered in accordance
with the present invention may vary, for example, depending on the
nature and/or extent of the desired outcome, on particulars of
route and/or timing of administration, and/or on one or more
characteristics (e.g., weight, age, personal history, genetic
characteristic, lifestyle parameter, severity of ischemic injury,
etc., or combinations thereof).
[0120] In some embodiments, an appropriate dose or amount is
determined in accordance with standard clinical techniques. For
example, in some embodiments, an appropriate dose or amount is a
dose or amount sufficient to reduce one or more symptoms by 1, 5,
10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90,
95, or 100%. In some embodiments, an appropriate dose or amount is
a dose or amount sufficient to maintain or prevent a decrease in
scores on a test for dementia. In some embodiments, an appropriate
dose or amount is a dose or amount sufficient to improve scores on
a test for dementia over a baseline score taken prior to initiation
of treatment. In some embodiments, an appropriate dose or amount is
a dose or amount sufficient to increase MMSE score over baseline by
1, 2, 3, 4, 5, 6, 7, 9, or 10 points.
[0121] In some embodiments, an appropriate dose or amount is a dose
or amount sufficient to maintain or prevent a decrease in MMSE
score. In some embodiments, an appropriate dose or amount is a dose
or amount sufficient to increase MMSE score over a baseline MMSE
score taken prior to initiation of treatment. In some embodiments,
an appropriate dose or amount is a dose or amount sufficient to
result in a blood concentration of from about 1 ng/mL to about 15
ng/mL, from about 1 ng/mL to about 10 ng/mL, from about 5 ng/mL to
about 15 ng/mL, or from about 5 ng/mL to about 10 ng/mL.
[0122] Alternatively or additionally, in some embodiments, an
appropriate dose or amount is determined through use of one or more
in vitro or in vivo assays to help identify desirable or optimal
dosage ranges or amounts to be administered.
[0123] Surprisingly, as shown by the examples disclosed herein,
VX-745 apparently exhibited a biphasic dose-response effect.
Without wishing to be bound by any theory, it is believed that high
levels of p38 MAPK activity may cause undesirably high
pro-inflammatory cytokine production whereas too low p38 MAPK
activity may cause an undesirable reduction of microglial activity.
In various embodiments, provided compositions are administered at a
therapeutically effective amount. As used herein, the term
"therapeutically effective amount" or "therapeutically effective
dosage amount" is largely determined based on the total amount of
the therapeutic agent contained in the pharmaceutical compositions
of the present invention. Generally, a therapeutically effective
amount is sufficient to achieve a meaningful benefit to the subject
(e.g., treating, modulating, curing, preventing and/or ameliorating
the underlying disease or condition).
[0124] In some embodiments, a composition is provided as a
pharmaceutical formulation. In some embodiments, a pharmaceutical
formulation is or comprises a unit dose amount for administration
in accordance with a dosing regimen correlated with achievement of
disease reduction in symptoms of dementia, arrest or decrease in
rate of decline of function due to dementia.
[0125] In some embodiments, a formulation comprising provided
compositions as described herein is administered as a single dose.
In some embodiments, a formulation comprising provided compositions
as described herein is administered as two doses. In some
embodiments, a formulation comprising provided compositions as
described herein is administered at regular intervals.
Administration at an "interval," as used herein, indicates that the
therapeutically effective amount is administered periodically (as
distinguished from a one-time dose). The interval can be determined
by standard clinical techniques. In some embodiments, a formulation
comprising provided compositions as described herein is
administered twice weekly, thrice weekly, every other day, daily,
twice daily, or every eight hours.
[0126] In some embodiments, a formulation comprising provided
compositions as described herein is administered twice daily. In
some embodiments, the twice daily administering occurs from about 9
to 15 hours apart. In some embodiments the twice daily
administering occurs about 12 hours apart. In some embodiments, a
formulation comprising from about 40 mg to about 250 mg of VX-745
is administered twice daily. In some embodiments, the administering
occurs when the patient is in a fed state. In some embodiments, the
administering occurs within 30 to 60 minutes after the subject has
consumed food. In some embodiments, the administering occurs when
the patient is in a fasted state. The administration interval for a
single individual need not be a fixed interval, but can be varied
over time, depending on the needs of the individual.
[0127] In some embodiments, a formulation comprising provided
compositions as described herein is administered at regular
intervals. In some embodiments, a formulation comprising provided
compositions as described herein is administered at regular
intervals for a defined period. In some embodiments, a formulation
comprising provided compositions as described herein is
administered at regular intervals for 2 years, 1 year, 11 months,
10 months, 9 months, 8 months, 7 months, 6 months, 5 months, 4
months, 3 months, 2 months, a month, 3 weeks, 2, weeks, a week, 6
days, 5 days, 4 days, 3 days, 2 days or a day.
Combination Therapies
[0128] In certain embodiments, the present invention provides a
method of treating dementia comprising administering to a subject a
dose of a p38 MAPK.alpha. inhibitor, such as VX-745, together with
one or more additional therapeutic agents. In some embodiments, the
present invention provides a method of treating dementia comprising
administering to a subject a therapeutically effective amount of
VX-745 in combination with one or more additional therapeutic
agents selected from cholinesterase inhibitors,
N-methyl-D-aspartate antagonists, vitamin E, antidepressants,
anxiolytics, antipsychotics, mood stabilizers and sleep aids. In
some embodiments, the present invention provides a method of
treating dementia comprising administering to a subject a
therapeutically effective amount of VX-745 in combination with one
or more therapeutic agents which target amyloid and/or tau protein.
In some embodiments, suitable therapeutic agents which target
amyloid and/or tau protein include, but are not limited to,
anti-amyloid antibodies (e.g., aducanumab), beta-secretase (BACE)
inhibitors, and tau aggregation inhibitors. In some embodiments the
tau aggregation inhibitor is selected from one or more of
methylthioninium chloride (MTC) and LMTX.RTM.. In some embodiments,
the present invention provides a method of treating dementia
comprising administering to a subject a therapeutically effective
amount of VX-745 in combination with a 5-HT.sub.6 antagonist. In
some embodiments, the present invention provides a method of
treating dementia comprising administering to a subject a
therapeutically effective amount of VX-745 in combination with
intravenous immunoglobulin (IVIg).
[0129] Representative cholinesterase inhibitors include, without
limitation, donepezil (Aricept.RTM.), rivastigmine (Exelon.RTM.),
galantamine (Razadyne.RTM.) and tacrine (Cognex.RTM.).
Representative antidepressants include, without limitation,
bupropion (Wellbutrin.RTM.), citalopram) (Celexa.RTM.), fluoxetine
(Prozac.RTM.), mirtazapine (Remeron.RTM.), paroxetine (Paxil.RTM.),
sertraline (Zoloft.RTM.), trazodone (Desyrel.RTM.), venlafaxine
(Effexor.RTM.), nortriptyline (Pamelor.RTM.) and desipramine
(Norpramine.RTM.). Representative anxiolytics include, without
limitation, lorazepam (Ativan.RTM.) and oxazepam (Serax.RTM.).
Representative antipsychotics include, without limitation,
aripiprazole (Abilify.RTM.), clozapine (Clozaril.RTM.), haloperidol
(Haldol.RTM.), olanzapine (Zyprexa.RTM.), quetiapine
(Seroquel.RTM.), risperidone (Risperdal.RTM.) and
ziprasidone)(Geodon.RTM.). Representative mood stabilizers include,
without limitation, carbamazepine (Tegretol.RTM.) and divalproex
(Depakot.RTM.). Representative sleep aids include, without
limitation, zolpidem, zaleplon and chloral hydrate. Representative
N-methyl-D-aspartate antagonists include, without limitation,
memantine (Namenda.RTM.).
EXEMPLIFICATION
[0130] The following examples are provided for illustrative
purposes and are not intended to limit the scope of the
invention.
Example 1
Objective
[0131] The purpose of this study was to evaluate the effects of
12-week oral twice-daily dosing on amyloid plaque load, as assessed
by quantitative dynamic [.sup.11C]PiB positive emission tomography
(PET) amyloid scanning, in patients with mild cognitive impairment
(MCI) due to Alzheimer's disease (AD) or with mild AD. Other
objectives included development of a PK/PD model for VX-745 and
amyloid plaque burden reduction, obtaining a preliminary evaluation
of the safety and tolerability of VX-745 in patients with MCI due
to AD or mild AD, and to evaluate the effects of VX-745 on synaptic
function, as assessed by memory assessment, magnetoencephalography
(MEG) and resting state fMRI. Exploratory cognitive endpoints
included MMSE and Wechsler Memory Scale (WMS).
Subjects
[0132] Subjects were men and women between 60-85 years old, having
a confirmed diagnosis of MCI due to AD or mild AD, a Mini-Mental
State Examination (MMSE) score between 20-28 (inclusive), and
demonstrated brain amyloid plaque load above a pre-determined
threshold as determined by PET scan and evaluation by radiologist.
FIG. 4 shows the patient demographic in this study.
Study Design
[0133] This was a phase IIa, single-center, multiple-dose,
open-label study of VX-745 (40 mg or 125 mg) administered twice
daily for 12 weeks in subjects with a confirmed diagnosis of mild
cognitive impairment or AD. Once eligibility was confirmed and
before the first dose of VX-745, subjects were randomly assigned to
one of two VX-745 dose groups and administered either 40 mg or 125
mg of VX-745, twice daily for 12 weeks. Investigators and patients
were blind to the dosage strength. VX-745 capsule(s) were
administered orally, twice daily with food for 12 weeks. Patients
were instructed to take doses within 30 minutes following a meal or
snack, with each dose taken approximately 12 hours apart at the
same times each day throughout the study. Baseline MMSE score was
measured in order to ensure that treatment with VX-745 did not
result in detrimental effects on MMSE score, mental status, and/or
mental function.
[0134] Dosing started on Day 1 following completion of all baseline
procedures. During the treatment period, subjects returned to the
clinic on Days 14, 28, 56, and 84. A follow-up visit was conducted
14 (.+-.3) days following the last dose of VX-745. Dynamic PET
scanning with full quantitative analysis was performed at baseline
and at the end of treatment.
[0135] Target engagement was assessed through the use of an
AD-related biomarker. The primary endpoint was based on assessment
of amyloid plaque burden using quantitative dynamic PET amyloid
scanning (Tolboom, N., et al. "Test-retest variability of
quantitative [.sup.11C]PIB studies in Alzheimer's disease." Eur. J.
Nucl. Med. Mol. Imaging 36(10): 1629-1638 (2009)). The method of
van Berckel et al (van Berckel B N, R. Ossenkoppele, et al.
"Longitudinal amyloid imaging using .sup.11CPiB: Methodologic
considerations." J. Nucl. Med. 54: 1570-1576 (2013)) was followed,
in which dynamic emission scanning consists of 23 frames with
progressive increases in frame duration (115, 35, 310, 230, 360,
2150, 2300, and 7600 s) for a total scan duration of 90 min; and
subsequently full quantitative data analysis of the images was
performed by reference parametric mapping (RPM2) using cerebellum
as reference tissue. This methodology allowed for a more reliable
(i.e. less variable) assessment of brain amyloid plaque load than
standard amyloid PET imaging. In addition this method of measuring
amyloid burden has high scan-to-scan stability (.about.2-3%
test-test variability) within subjects. No placebo group was
enrolled. Instead, reductions in brain amyloid plaque load of
greater than 7%, which is definitively outside the range of
test-test variability, were considered to be a drug effect in this
study.
[0136] Two VX-745 doses were selected: 40 mg and 125 mg. VX-745
exposure observed in the brains of animals is approximately
1.7-fold higher than in peripheral blood.
[0137] As the primary objective of this study was to assess effects
on amyloid plaque load as assessed by quantitative dynamic
[.sup.11C]PiB (carbon-11 labeled Pittsburgh Compound B) amyloid PET
scanning, the major subject inclusion criteria for this study was
having evidence of elevated brain amyloid plaque load by PET
scanning; otherwise patients with either MCI due to AD or mild AD
were included. A lower limit of MMSE score of 20 was included in
order to not enroll patients with more advanced cognitive decline,
in whom any potential deleterious effects of VX-745 on function
would be more difficult to ascertain.
[0138] MEG and resting state fMRI are conducted to obtain initial
data on the effects of p38 MAPK inhibition by VX-745 on
neuronal/synaptic function. These data can be utilized for design
of additional studies that are longer in duration, larger in size,
and placebo-controlled in order to further assess treatment effects
of VX-745 on these measures.
[0139] Normal cognitive function in humans relies on the
integration of dynamic communication between brain regions. Viewing
the brain as a functional network may serve as an intermediate
phenotype between pathology and clinical symptoms. Functional brain
networks of healthy individuals are organized according to a highly
efficient topology that optimizes local connectivity with long
distance integration. In Alzheimer's Disease, among other brain
diseases, changes in functional connectivity between brain regions
and disruption of higher order organization of functional brain
networks are seen. To measure functional connectivity and network
topology, several techniques can be used, including MEG and
rs-fMRI. MEG is predominantly based on the magnetic field of the
summation of synaptic currents in the dendritic trees of cortical
pyramidal cells, whereas fMRI measures blood oxygenation related to
the levels of neural activity. Both techniques are patient friendly
and have a high spatial resolution, which enables the investigation
of detailed network analysis. These techniques can be used to
measure VX-745 effect on the relative preservation or improvement
of brain function, providing a biological indicator for study
effects.
[0140] In this study, episodic memory was evaluated using the Dutch
version of the WMS scale utilizing both verbal and visual
information: Logical Memory (LM I & II) test, in which subject
is read a story; Verbal-Paired Associates (VPA I & II), in
which subject is given pairs of words and asked remember which
words go together; and Visual Reproduction (VR I & II)), in
which subject is given drawings of specific shapes. Subjects were
then asked to recall the information within each test both in an
immediate (WMS-Immediate Recall composite) and delayed (WMS-Delayed
Recall composite) basis The total score of the WMS-Immediate Recall
component could range from 0 to 136 (0-53 for LMI; 0-40 for VPA I,
and 0-43 VR I) and for the WMS-Delayed Recall from 0 to 92 (0-39
for LM II; 0-10 for VPA II, and 0-43 VR II).
[0141] The 12-week treatment duration is several-fold longer than
the 10-14 day treatment duration in animal studies of agents that
demonstrated reduction in brain amyloid plaque load, including
VX-745; 12-week treatment duration also provides a sufficient
duration to assess tolerability in advance of larger and longer
duration studies that would assess effects on mental status and
memory function. A table summarizing the time schedule of patients
assessments is provided in Table 1:
TABLE-US-00001 TABLE 1 Schedule of assessments Screening Screening
Treatment Period (Visit No.).sup.a Visits (Study Day) Assessment
Visit 1.sup.a 2.sup.a 3.sup.b 4 5 6 7 Follow- Day Up D -21 to D 0 1
14 28 56 84 Visit.sup.c Informed Consent .sup. X.sup.d Medical
history review X Prior/concomitant X X X X X X X X medication
Physical examination.sup.e X X X.sup.f Adverse events X X X X X X X
X recording.sup.g Clinical laboratory X X X X X X X sampling.sup.h
12-lead electro- X X cardiogram.sup.i Magnetoenceph- X X X X.sup.f
alography (MEG).sup.j MMSE.sup.k X X X X X X WMS (Immediate and X X
X X.sup.f Delayed Recall).sup.k Dynamic .sup.11C-PiB PET X X
X.sup.f scanning and resting state fMRI.sup.l Dispense study
drug.sup.m X X X Pharmacokinetic X X X X sampling.sup.n Plasma Tau
and NFL X X X X Final study drug X X.sup.f reconciliation.sup.m
DSS: Dementia Signs and Symptoms Scale; MMSE: Mini-Mental State
Examination; WMS: Wechsler Memory Scale; PET: positron emission
tomography. .sup.aTwo screening visits are planned to allow most
screening procedures to be completed and reviewed during the first
visit before Dynamic Amyloid PET scan is performed. All screening
assessments should be conducted within 21 days of Day 1. .sup.bOn
Day 1, all procedures should be conducted prior to first dose of
VX-745. .sup.cFollow-up Visit should be conducted within 14 (.+-.3)
days of the last dose of VX-745 for subjects who complete the study
or discontinue early. .sup.dInformed consent procedures, including
signing of informed consent, must be completed before any study-
specific procedures are performed. .sup.eRefer to Section 8.1.6 for
details regarding physical examination .sup.fThese assessments will
be performed at Follow-up Visit only for subjects who discontinue
treatment prematurely and after day 14. .sup.gDefinitions and
procedures for documenting and reporting adverse events and serious
adverse events are provided in Sections 8.1.10 and 8.1.10.3.
.sup.hDetails of clinical laboratory sampling for chemistry and
hematology parameters are discussed in Section 8.1.8. .sup.iDetails
of 12-lead ECG assessment are discussed in Section 8.1.7.
.sup.jDetails of MEG are discussed in Section 8.1.2.2. .sup.kRefer
to the following sections for details of cognitive assessments
Section 8.1.3.1 (MMSE), and Section 8.1.4.4 (WMS - Immediate and
Delayed Recall). .sup.lPerformed concurrently on same machine;
refer to Section 8.1.2.1 for details regarding 11C-PiB F18 PET scan
and resting state fMRI evaluation. .sup.mStudy drug details
including packaging, storage, accountability, and dosing are
presented in Section 7.4. .sup.nThe time of the PK sampling and the
time of the last administered dose must be recorded. Refer to
Section 8.1.5 for details regarding PK sampling.
Results
[0142] Sixteen subjects completed the full 12 weeks of treatment
and all were included in safety analyses. VX-745 was well
tolerated. No serious adverse events were observed. FIG. 5 shows
incidence of adverse events. No liver transaminase elevations were
observed. In the PK analysis, due to the sparse sampling collection
design, the time period from 0 to 24 hours post-dose was divided
into 4 blocks in order to show the distribution of concentrations
over time. In both dose groups, the time of VX-745 C.sub.max
(T.sub.max) was mostly observed in the 3 to 4 hours post-dose
interval. Table 2 illustrates the summary statistics for VX-745
plasma concentration values. Average blood concentration of about 8
ng/mL at the 40 mg dose level was observed. This is higher than the
5 ng/mL VX-745 IC.sub.50 for inhibition of p38 MAPK.alpha. enzyme
activity. Population pharmacokinetic analyses that combined results
from this study and the study in Example 2 demonstrated a median
12-hour exposure of 78 ng*hr/mL for the 40 mg dose level and 116
ng*hr/mL for the 125 mg dose level; and a terminal half-life of
approximately 16 hours.
TABLE-US-00002 TABLE 2 Summary Statistics of VX-745 Plasma
Concentration Values Overall and for Each Dose Group by Post-dose
Collection Time Interval VX-745 Plasma Concentration (ng hr/mL)
Time Me- Group (hours) N dian Min Max Mean SD 25.sup.th 75.sup.th
40 mg <3 6 7.66 5.43 19.10 9.77 5.09 6.84 11.07 3 to 4 7 10.40
6.18 22.10 11.62 4.96 9.99 11.35 >4 to 13 7.02 2.35 18.20 7.59
4.23 5.10 7.59 <6 .gtoreq.6 9 4.39 3.01 8.38 4.95 1.59 4.15 4.83
125 mg <3 7 22.10 9.88 50.10 24.97 14.47 14.15 32.20 3 to 4 5
23.80 17.70 36.20 24.16 7.30 19.00 24.10 >4 to 13 14.30 1.84
35.10 15.37 8.54 11.40 17.70 <6 .gtoreq.6 3 9.30 5.96 20.80
12.02 7.78 7.63 15.05 All <3 13 13.10 5.43 50.10 17.95 13.33
8.26 22.10 3 to 4 12 14.95 6.18 36.20 16.85 8.63 10.30 22.53 >4
to 26 10.55 1.84 35.10 11.48 7.70 6.42 16.10 <6 .gtoreq.6 12
4.80 3.01 20.80 6.72 4.80 4.29 7.01
[0143] FIG. 1 depicts exemplary mini MMSE parameters used in the
study to assess patients to determine level of mental function.
[0144] FIG. 2 depicts an exemplary graph of absolute change in MMSE
scores of four patients, treated with either 40 mg or 125 mg
VX-745. As shown in FIG. 2, two of four patients in the 40 mg group
surprisingly exhibited greater than a 3-point improvement in MMSE
score over baseline. This finding was very surprising as no
disease-modifying drug to date has shown any level of improvement
in MMSE score, mental status, and/or mental function. Rather, at
best all that was expected was a slowing in the rate of decline of
mental function seen with dementia, particularly dementia
associated with Alzheimer's disease. Without wishing to be bound by
any theory, it is thought that treatment with VX-745 may enhance
synaptic plasticity, stabilize and/or reverse synaptic loss, and
preserve or improve neuronal function.
[0145] By observation of the descriptive MMSE data, modest changes
were evident over the course of treatment. At Day 84 (Visit 7),
approximately 50% of subjects in the 40 mg group and 33% of
subjects in the 125 mg group had an increase from screening of at
least 1 in MMSE score.
[0146] FIG. 6 panels A-C depict changes in MMSE scores for eight
patients treated with 40 mg and seven patients treated with 125 mg
VX-745.
[0147] Further analysis included Wechsler Memory Scale (WMS)
Analyses. The WMS includes three subcategories: immediate recall,
delayed recall, and symbol span, each with distinct assessments.
Results can be analyzed as two distinct composites scores or as an
overall composite score. This evaluation included the overall
(score range: 0 to 401), immediate recall (score range: 0 to 136),
and delayed recall (score range: 0 to 92) composite scores; the
latter two are considered measures of episodic memory. In addition,
the Symbol Span sub-component of WMS was analyzed separately (score
range: 0 to 50). In all cases, higher scores reflect better
cognitive performance.
[0148] Mean Wechsler Memory Scale (WMS) immediate recall composite
scores increased from 48.4 (.+-.3.8) at baseline to 58.4 (.+-.4.3)
at Day 84 (n=15; p=0.005 by Wilcoxon sign rank test for
improvement). Mean WMS delayed recall composite scores increased
from 13.2 (.+-.2.3) at baseline to 22.1 (.+-.4.1) at Day 84
(p<0.001). For immediate recall composite score, 7 of 8 patients
in the 40 mg group and 6 of 7 in the 125 mg group showed
improvement from baseline and, for delayed recall composite score,
8 of 8 patients in the 40 mg group and 6 of 7 in 125 mg group
showed improvement from baseline.
[0149] P-values based on Wilcoxon-signed rank one-sided test for
median change from baseline are presented in Table 3. Statistically
significant improvement (P value<.alpha. at 0.05 level) was
observed for combined dose groups (N=15) for all composite scores
on Day 84. The increase from baseline to Day 84 in overall
composite score was statistically significant individually for the
40 mg (P=0.021) and 125 mg (P=0.017) groups, and for
immediate-recall composite within 125 mg group (P=0.026), and for
delayed-recall composite within 40 mg (P=0.007) and 125 mg groups
(P=0.013); a trend (P=0.054) was seen for 40 mg dose for
immediate-recall composite change from baseline to Day 84. Episodic
memory measures within the WMS showed improvement. All
subcomponents of WMS episodic memory composites showed
statistically significant (P<0.05) increases at Day 84.
TABLE-US-00003 TABLE 3 P-Value for Testing Wechsler Memory Scale
Median Increase from Baseline in Composite Scores (Immediate
Recall, Delayed Recall, and Overall) and Symbol Span by Visit and
Treatment P-value Score Visit 40 mg 125 mg All Immediate Recall
Composite 5 (Day 28) 0.200 0.037 0.028 7 (Day 84) 0.054 0.026 0.005
Delayed Recall Composite 5 (Day 28) 0.007 0.071 0.001 7 (Day 84)
0.007 0.013 0.000 Symbol Span 5 (Day 28) 0.612 0.011 0.116 7 (Day
84) 0.879 0.304 0.546 Overall Composite 5 (Day 28) 0.080 0.011
0.003 7 (Day 84) 0.021 0.017 0.002 Note: P-value is based on
Wilcoxon signed rank test that tested for improvement (1-sided)
[0150] FIG. 7 shows Wechsler Memory Scale (WMS) Analyses. Cognitive
analysis showed dose dependent improvement on immediate and delayed
recall in nearly all patients, regardless of effect on amyloid
plaque. (A) shows three subsets of the WMS test (Logical Memory,
Visual Reproduction, and Verbal Paired Associates) and associated
point-based performance scores for immediate recall and delayed
recall indices. (B) depicts the Immediate Recall mean scores for
subjects administered 40 mg or 125 mg VX-745. Improvement from
baseline at day 84 was observed in 7 of 8 patients in the 40 mg
group and 6 of 7 in the 125 mg group. (C) depicts the Delayed
Recall mean scores. Improvement from baseline at day 84 was
observed in 8 of 8 patients in the 40 mg group and 6 of 7 in the
125 mg group. Analyses were done by Wilcoxon sign rank test for
improvement.
[0151] PK-PD modeling demonstrated that exposure (AUC) of VX-745
was a statistically significant variable for predicting the change
from baseline to Day 84 in combined WMS immediate and delayed
recall score. Plasma drug levels explained 70% (i.e., r.sup.2=0.70;
P=0.0001) of the variance in change (improvement) from baseline to
end-of-treatment. Therefore, PK-PD correlation (linear-regression
model) indicated individual subject plasma drug concentration
profiles were significantly correlated to change in combined WMS
immediate- and delayed-recall. These data strongly argue that the
improvement seen in episodic memory in this study was primarily due
to VX-745 treatment, and not due to chance or practice effects.
[0152] FIG. 8 depicts responder analysis of dynamic [.sup.11C]PiB
PET. Response is defined by % Change RPM2 BPND parameter from
quantitative analysis of dynamic PET Scan. On 40 mg, 3 subjects
reached the 7% responder criterion and 2 subjects were between 3
and 7%. Subject with response on 125 mg had the lowest plasma drug
exposure in that group; drug exposure in this subject approximated
that in 40 mg dose group.
[0153] The heterogeneous response is consistent with the model in
which the primary relevant pharmacological effect is a decrease in
amyloid plaque production, which in the context of efficient
endogenous clearance would lead to reduced brain amyloid plaque
load. However, the level of endogenous clearance will vary for
patient to patient. Consistent with this hypothesis the responders
were all patients with lower levels of baseline brain amyloid
plaque load less than the median for the study, as these would be
the patients that would be expected to have higher endogenous
amyloid plaque clearance levels at study entry.
[0154] Percentage reduction in global cortical RPM2-BPND in the 3
responders in the 40 mg dose group was -11.6%, -11.9%, and -40.5%,
respectively, and in the one responder in the 125 mg dose group was
-7.7%. Results were similar for response rate for all regional
measurements of PET metrics. Table 4 summarizes responders.
TABLE-US-00004 TABLE 4 Number of Responders by PET Metric and Dose
Group and Overall Number of Responders.sup.a/Total Number in
Population PET Metrics 40 mg 125 mg All Global 3/8 1/7 4/15 Frontal
3/8 1/7 4/15 Med Temp Lobe 4/8 2/7 6/15 Temporal 2/8 1/7 3/15
Cingulate Posterior 2/8 0/7 2/15 Parietal 3/8 0/7 3/15 Source:
Listing 16.2.6.1 .sup.aResponder was defined as reduction of
.gtoreq.7% in PET metrics (RPM2-BPND).
[0155] FIG. 9 depicts analysis of quantitative dynamic
[.sup.11C]PiB PET. Shown are RPM2 BPND parameters from quantitative
analysis of dynamic PET Scan. Percent change in global cortical PET
amyloid signal versus baseline signal is depicted for <90
.mu.g*hr/mL and >90 .mu.g*hr/mL in a 12-hour plasma exposure to
VX-754. Responders are shown as circles with vertical lines.
Potential explanations for lack of effect at <90 .mu.g*hr/mL at
high baseline cortical PET signal may indicate high plaque loads
outside the dynamic range of the test and/or 3-month treatment
duration that is not sufficient for effect on higher plaque
loads.
[0156] FIG. 15 depicts plasma brain-derived neurotrophic factor
(BDNF) levels at baseline and after 84 days (n=10 subjects). BDNF
levels were measured by Somascan.RTM.. (A) shows individual subject
BDNF levels. (B) shows mean BDNF levels. These results indicate
that VX-745 at this dose increases plasma BDNF levels in
humans.
Example 2
Objective
[0157] The purpose of this study was to assess the pharmacodynamic
(PD) activity of VX-745 in the central nervous system of patients
with mild cognitive impairment (MCI) due to Alzheimer's disease
(AD) or with mild AD. Other objectives included evaluating the
safety and tolerability of VX-745 at doses of 40 and 125 mg twice
daily for 6 weeks (42 days) in patients with a confirmed diagnosis
of mild cognitive impairment due to AD or with mild AD and
evaluating the plasma and cerebrospinal fluid (CSF) pharmacokinetic
profile of VX-745 at doses of 40 and 125 mg administered twice
daily for 6 weeks (42 days) in patients with a confirmed diagnosis
of MCI due to MD or with mild AD. Exploratory cognitive endpoints
included Hopkins Verbal Learning Test-Revised (HVLT-R) and
MMSE.
Subjects
[0158] Subjects were men and women between 60-85 years old, having
a confirmed diagnosis of MCI due to AD or mild AD (consistent with
National Institute of Aging and Alzheimer's Association research
diagnostic guidelines) and a Mini-Mental State Examination (MMSE)
score greater than 20. Inclusion criteria included gradual and
progressive decline in memory function reported by patients or
informants over more than 6 months; an amnestic presentation on
formal neuropsychological testing that was characterized by a
pattern of rapid forgetting, as determined by the
PI/subinvestigator; evidence of functional decline as evidenced by
a CDR sum of box score of .gtoreq.0.5; and MMSE score of 17 to 30,
inclusive. FIG. 10 shows the patient demographic in this study. A
total of 9 subjects were enrolled and all were included in safety
analysis; 8 subjects completed 6 weeks treatment and were included
in pharmacodynamics analysis. As plasma drug concentration in the
one subject who received 125 mg was similar to the remaining study
subjects, this subject's data were pooled with the remaining
subjects in all analyses.
[0159] Study Design
[0160] This is a phase IIa, single center, multiple-dose,
open-label study of VX-745 (40 mg or 125 mg) administered twice
daily with meals for 6 weeks (42 days) in subjects with a confirmed
diagnosis of mild cognitive impairment due to AD or mild AD. Once
eligibility was confirmed and before baseline CSF sampling,
subjects were randomly assigned to one of two VX-745 dose groups
and administered either 40 mg or 125 mg of VX-745, twice daily for
12 weeks. Investigators and patients were blinded to the dosage
strength. The first 3 patients were randomly assigned to receive
either 40 or 125 mg twice daily, with dosing level blinded. The
remaining patients (up to 7 patients) received 40 mg twice daily on
an open-label basis. After the baseline CSF sampling, VX-745
capsule(s) were administered orally, twice daily with food for 6
weeks. Patients were instructed to eat a meal approximately 30
minutes before dosing with VX-745, with each dose taken
approximately 12 hours (+/-3 hours) apart at the same times each
day throughout the study.
[0161] Cytokine measurements of CSF samples were done to assess the
balance of pro-inflammatory versus anti-inflammatory cytokines. The
t-helper type 1/t-helper type 2 (TH1/TH2) multiplex cytokine
(IFN-.gamma., IL-1.beta., IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70,
IL-13, TNF.alpha.) panel by Mescoscale Discovery were utilized to
inform on effects on the relative balance of pro-inflammatory
cytokines (e.g. IL-1.beta., TNF.alpha.) versus anti-inflammatory
cytokines (e.g., IL-10).
[0162] Effects on CSF levels of A.beta. peptides were evaluated as
measures of the amyloidenic process, which is activated with aging
and more so in patients with Alzheimer's disease.
[0163] Phospho-tau and NFL proteins from CSF sampling were
evaluated as markers of the effects of inflammation on
neurodegeneration and axonopathy, respectively. The CSF-NFL marker
has been demonstrated in other neuro-inflammatory disease contexts
to be a sensitive and specific marker of inflammation-induced
axonal damage.
[0164] Butylcholinesterase expression on microglia has been
demonstrated in animal studies and in human brain to be associated
with pro-inflammatory microglial activation, and CSF measurements
of butylcholinesterase were available as indirect measures of
activation in the brain. Quantitative EEG was conducted as a
measure of the effects of inflammatory cytokines on synaptic
function and the effects of modulation of p38 MAPK on synaptic
plasticity. Brain fluorodeoxyglucose (FDG) PET scan was conducted
at the Screening Visit and Day 40 to measure brain metabolism. In
addition, CSF drug levels of VX-745 were obtained to confirm
delivery of drug to the brain.
Results
[0165] VX-745 was well-tolerated. No safety concerns were
identified. One subject discontinued within the first week because
of headache and vomiting, attributed to persistent CSF leak after
baseline CSF collection. Most common adverse events included mild
dizziness, headache, and somnolence reported in 2 subjects each.
There were no treatment-related or clinically relevant trends for
any of the safety laboratory or 12-lead ECG parameters.
[0166] Plasma pharmacokinetics indicated that average blood drug
concentration (CAvG) at 40 mg was 8 ng/mL and Cmax was 23 ng/mL. A
weight of <57 kg was associated with higher plasma drug
concentrations. The terminal half-life was 10 hours. CSF drug
levels were 6% of plasma drug levels at the same time point. This
was consistent with preclinical CSF PK data, which were associated
with brain concentrations two-fold higher than that in blood. Thus,
VX-745 concentrations in the brain are expected to be at .about.14
ng/mL (.about.30 nM), which is the concentration that can inhibit
IL-1.beta. signaling.
[0167] Target engagement was assessed through the evaluation of the
effect of drug treatment on CSF biomarkers. CSF was collected at 6
time-points over 24 hours at baseline (the 24 hours prior to first
dose) and again at 6 time-points over 24 hours near the end of
treatment on Day 40. The samples were evaluated by the Mesoscale
Discovery ELISA platform for multiple cytokines ((IFN-.gamma.,
IL-1.beta., IL-2, IL-4, IL-5, IL-8, IL-10, IL-12 protein 70, IL-13,
TNF.alpha., and CSF) and for amyloid-beta peptides
(A.beta.38/40/42).
[0168] FIG. 11 depicts CSF interleukin-10 (IL-10) mean change from
baseline on day 41 with time-matched day 42 plasma concentration.
CSF IL-10 decreased rapidly after VX-745 reached Cmax in the
plasma. The decrease appears to increase with dose; however, there
is only 1 patient at 125 mg.
[0169] Of the cytokines evaluated, only IL-8 and TNF.alpha. were
consistently detectable in all subjects. For each there was a
statistically significant correlation (p=0.004 and p=0.04,
respectively) between plasma drug concentration and suppression of
peak levels at the Day 40.
[0170] Separating patients into high and low exposure groups based
on plasma AUC.sub.(0-8) on Day 1, comparison concentrations at
matched time points at Day 41 to baseline lead to a trend towards
lower CSF IL-8 in the high exposure group. FIG. 12 depicts
interleukin-8 (IL-8) levels (pg/mL) in CSF over 24 hours at
baseline and at day 41.
[0171] For A.beta. 38/40/42, there was a statistically significant
correlation (p=0.01 to p=0.047) between plasma drug concentration
and increases from baseline to Day 41 in levels of each A.beta.
peptides.
[0172] The combined effect of a reduction of CSF inflammatory
markers and an increase in CSF A.beta. peptides suggests that
higher plasma drug concentrations (AUC.sub.0-12>120 ng*hr/mL)
leads to inhibition of microglial activation. Inhibition of
microglia activation may explain why the 125 mg dose level appeared
to not be effective in reducing brain amyloid plaque load in
Example 1.
[0173] The Hopkins Verbal Learning Test-Revised (HVLT-R) was
utilized to assess episodic memory. In this test, 12 specific words
from a list were provided verbally, and the subject was asked to
recall as many words as possible. Two scores are calculated: (i)
Total (Immediate) Recall Score (range: 0-36): combined score of
three consecutive trials immediately following provision of words
and (ii) Delayed Recall Score (range: 0-12): Number of words
recalled when subject was asked 20 to 25 minutes after initial
trials to recall as many of the words originally provided. A
strength of the HVLT-R is that six different validated version
exist that each incorporate a different set of words. Due to the
use of these different versions during the course of a clinical
study, there is essentially no practice effect with repeated
administration (Benedict, R. H. B. et al, "Hopkins Verbal Learning
Test-Revised: Normative Data and Analysis of Inter-Form and
Test-Retest Reliability." The Clinical Neuropsychologist, 12(1):
43-55 (1998)).
[0174] Mean Total Recall improved from 19.1 (.+-.1.5) at Baseline
to 22.6 (.+-.2.1) at week 6 (p=0.015 for improvement from
baseline); Delayed Recall increased from 5.4 (.+-.0.6) to 7.5
(.+-.1.1) (p=0.028 for improvement from baseline). Median increase
in Total Recall score was 4.5 (range: -2.5 to +9.5), with only one
subject with a decrease during treatment. Particularly with the use
of alternate versions that should minimize "placebo effects", the
consistency of improvement and statistics indicates that the
improvements in episodic memory seen in this study are due to
VX-745 treatment (Table 5).
TABLE-US-00005 TABLE 5 Hopkins Verbal Learning Total Recall,
Delayed Recall, Retention and Recognition Scores Change from
Averaged Baseline - Overall (Pharmacodynamic Population) HVLT-R 90%
CI 90% CI Score Arithmetic Lower Upper P Visit n Mean SD Bound
Bound Value Minimum Median Maximum Total Recall Day 14 8 0.6 2.62
-1.13 2.38 0.2604 -2 0.0 6 Day 40 8 3.5 3.61 1.08 5.92 0.0143 -3
4.5 10 Delayed Recall Day 14 8 0.8 1.83 -0.48 1.98 0.1425 -3 1.0 4
Day 40 8 2.1 2.62 0.37 3.88 0.0276 0 1.0 7 Retention (%) Day 14 8
3.8 24.50 -12.66 20.16 0.3390 -37 6.3 35 Day 40 8 15.3 26.61 -2.58
33.08 0.0746 -14 6.5 71 RDI Day 14 8 -0.1 2.28 -1.65 1.40 >0.5
-3 -0.3 5 Day 40 8 -1.3 5.82 -5.15 2.65 >0.5 -11 1.3 6 CI =
confidence interval for the mean; P value: statistical significance
(1-sided) for test that paired mean difference is improved
(increased) versus a null hypothesis of no improvement; RDI =
Recognition Discrimination Index; SD = standard deviation; n =
number of patients in the specific population Baseline is the
average of Screening and Day -2.
[0175] FIG. 13 depicts Hopkins Verbal Learning Test-Revised
(HVLT-R) analyses. (A) shows mean group scores for HVLT-R total
recall. For each subject, baseline is calculated as an average of
the screening and day -2 value (n=8). During screening (dates -28
to -3), patients underwent eligibility procedures, including
screening for concomitant medications and medical assessments
including vital signs, 12-lead electrocardiogram, physical exam,
clinical laboratory testing, and FDG PET scan. On day -2, in
screening procedures were repeated, but instead of FDG PET scan,
patients were given quantitative electroencephalogram (qEEG),
Hopkins Verbal Learning Test-Revised (HVLT-R) and Columbia-Suicide
Severity Rating Scale (C-SSRS). (B) shows individual subject scores
for HVLT-R total recall. (C) shows mean scores for HVLT-R total
recall. (D) shows mean group scores for HVLT-R delayed recall. For
each subject, baseline is calculated as an average of the screening
(days -28 to -3) and day -2 value (n=8). (E) shows individual
subject scores for HVLT-R delayed recall. (F) shows mean scores for
HVLT-R delayed recall.
[0176] To further evaluate and compare the episodic memory results,
within-subject treatment effect sizes (ES; called Cohen's d in
statistics) were calculated for each study (Example 1 and Example
2)/measure. The results are shown in Table 6.
TABLE-US-00006 TABLE 6 Calculated Treatment Effect Sizes. Example 1
study (N = 15) Example 2 study (N = 8) (Wechsler Memory Scale)
(HLVT-R) Immediate Recall .59 .69 Delayed Recall .69 .86
[0177] The within-subject effect size (ES) calculations show first
that the results are very similar between the two studies, i.e.
there is a high degree of consistency between the studies despite
the use of different measures and tests being applied in different
languages/cultures. The magnitude of the ES ranging between 0.59
and 0.86 also argues for a true drug effect as in MCI and AD
patient population ES for improvement in placebo groups when they
are seen are less than 0.3 (Goldberg et al, 2015), and often show
either no change or worsening (Scheltens et al, 2011; Hassenstab et
al, 2015).
[0178] In addition, as ES>0.5 is generally taken as being
clinically meaningful, ES calculations allows an assessment of
whether the magnitude of treatment effect is clinically relevant;
which in the current clinical studies with VX-745 appears to be so.
An ES relative to placebo-treatment may be determined with a
randomized-double-blind placebo-controlled study.
[0179] FIG. 14 depicts MMSE individual subject scores at baseline
and day 40. Although the variability in MMSE results and the sample
sizes tdo not allow statistical analyses, the overall trends are
encouraging. CSF levels of neurofilament light chain (NFL) and
butylcholinesterase showed no change from baseline to day 40FDG-PET
showed no change from baseline to day 40. EEG showed potential
positive pharmacodynamics effect.
Example 3
Objective
[0180] A six-month study is performed to establish that VX-745 can
improve mental functions impaired by dementia. Fifty (50) to 100
patients diagnosed with MCI or dementia associated with Alzheimer's
disease are assigned to each treatment arm: placebo vs. 40 mg of
VX-745.
[0181] Subjects
[0182] Subjects are men and women with clinically diagnosed late
MCI or mild Alzheimer's disease, having MMSE score above 20, FSCRT
free recall below 20, total recall below 40 (i.e., meets
objectively defined amnestic criteria), and positive AD-related CSF
biomarkers (CSF A.beta.1-42/A.beta.1-40 and p-tau (or total tau)
above a pre-determined threshold).
Study Design
[0183] This is a randomized double-blind placebo-controlled study
of VX-745 (40 mg or placebo) administered twice daily with food for
24 weeks.
[0184] Primary endpoints include change in verbal episodic memory
immediate and delayed recall, in VX-745-treated patients compared
to that in placebo recipients.
[0185] Secondary endpoints include change in WMS
verbal-paired-associations and visual reproduction,
immediate/delayed recall and recognition; MMSE; CDR-SOB; CSF
biomarkers (total tau, p-tau, A.beta.40, A.beta.42).
Example 4
[0186] The present example demonstrates effects of VX-745 in
reducing EEA1-labeled early endosome numbers and size in a model in
vitro system for dementia.
[0187] Down's Syndrome (DS, Trisomy 21) derived human fibroblasts
provide a robust system for studying Alzheimer's related endosomal
dysfunction as one of the Familial Alzheimer's disease (FAD) genes,
Amyloid Precursor Protein (APP), is expressed on chromosome 21 and
as a result inherently DS individuals overexpress APP and develop
an Alzheimer's type dementia as they grow older beyond age 40
(Jiang, Y. et. al., "Alzheimer's-related endosome dysfunction in
Down syndrome is A.beta.-independent but requires APP and is
reversed by BACE-1 inhibition," PNAS 107:1630-1635 (2010)).
[0188] In vitro, DS human fibroblasts show increased numbers and
enlarged early endosomes by electron microscopy or by fluorescence
staining with antibodies to EEA1 (Early Endosome Antigen 1). 2N and
DS (Down's Syndrome) human fibroblasts were incubated with 0, 1,
10, or 50 nM of VX-745 for 24 hours. After incubation, the cells
were fixed and incubated with anti-EEA1 antibody to label early
endosomes. FIG. 16 depicts EEA1 positive endosomes in 2N
(Wild-Type) or DS (Down's Syndrome) human fibroblasts after 24
hours exposure to VX-745. (A) Shows average number of EEA1-labeled
endosomes per cell was higher for DS versus 2N cells and incubation
with VX-745 significantly reduced the average number EEA1-labeled
endosomes per DS cell. (B) Shows average size of EEA1-labeled
endosomes was significantly reduced in DS cells after incubation
with VX-745.
EQUIVALENTS AND SCOPE
[0189] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. The scope of the present invention is not intended to be
limited to the above Description, but rather is as set forth in the
following claims:
* * * * *